BACKGROUND: T-box transcription factor 4 (TBX4) is a critical regulator of lung and pulmonary vascular development. Pathogenic TBX4 variants are associated with developmental lung disease, pulmonary hypertension, and neonatal respiratory failure. CASE PRESENTATION: We report two siblings with lethal neonatal respiratory failure. The first, a term female infant, died at 11 h of life, and her late-preterm male sibling died at 9 h despite maximal intensive care. Both developed severe hypoxemia and pulmonary hypertension. Autopsy demonstrated marked pulmonary hypoplasia. Whole-exome sequencing identified a novel heterozygous TBX4 variant, c.741G>C (p.Lys247Asn), inherited from their unaffected father. Preimplantation genetic testing detected the variant in seven of 10 embryos. CONCLUSION: These cases expand the spectrum of TBX4-associated developmental lung disease and support consideration of TBX4 testing in neonates with unexplained respiratory failure and pulmonary hypertension.